studio di «real world» practice Olaparib come mantenimento nella recidiva BRCAmut platino sensibile di carcinoma ovarico: studio di «real world» practice

BACKGROUND In patients with platinum-sensitive recurrent OC, re-challenge with platinum is considered a vali­dated approach.1 Maintenance therapy with active and well-tolerated anti­neoplastic drugs is a useful modality to consolidate and prolong tumor responses, delaying disease progression and deferring subsequent treatments. In December 2014, Olaparib obtained regulatory approval in the EU as maintenance monotherapy for patients with platinum-sensitive recurrent (PSR) BRCAm (germline and/or somatic) HGSOC, fallopian tube or primary perito­neal cancer, who gained complete response (CR) or partial response (PR) after last platinum-based chemotherapy.2 This EU approval was based on the results of a random­ized, double-blind, placebo-controlled, phase II study (STUDY 19) (12), in which maintenance monotherapy with olaparib (capsules) significantly prolonged progres­sion-free survival (PFS) compared to placebo in patients with PSR HGSOC (8.4 vs 4.8 months, hazard ratio [HR] 0.35; p <0.001). This clinical benefit was significantly greater in the subgroup of BRCAm patients (11.2 vs 4.3 months, HR 0.18; p<0.0001), with a trend toward im­proved overall survival (OS) (HR 0.62, 95% CI 0.41-0.94) that not reached the statistically significance. The trial was not designed to assess OS, nevertheless, also in the overall population studied, patients who received olaparib main­tenance therapy had a non-statistically significant greater OS (HR 0.73, 95% CI 0.55-0.96) compared to control arm (p<0.0095). 1, Pignata S, et al; J Clin Oncol. 2017 2. EMA. Lynparza recommended for approval in ovarian cancer. http://www.ema.europa.eu/ema/index.jsp?curl=pages/ news_and_events/news/2014/10/news_detail_002196. jsp&mid=WC0b01ac058004d5c1

RATIONALE Patients enrolled in clinical trials are favourably selected There isn’t any report published in extenso in literature about the real use of olaparib in the clinical practice. Anemia and nausea are very common AEs and their management is not well codified The use of dose reductions based on toxicity has been poorly described Very few data about the efficacy of further treatments after PARPi

Olaparib Real World data First real life data on Olaparib in BRCA1/2 mutated Platinum-Sensitive relapsed EOC in France: analysis of 51 pts. 31 centres. May 2014-March 2015 Results: 14 pts (28.6%) treated >3 months 4 pts (8.2%) >6 months collection of safety data= ongoing 6 pts (11.8%) discontinued olaparib (3 pts for AE/ADRs+2 for PD+ 1 for aggravation of a previous leiomyosarcoma) 88% of pts still treated T. De La Motte Rouge et al, EJC sep. 2016 Volume 51, Supplement 3, Pages S548–S549

Olaparib prospective Real World trials C-PATROL Non-interventional study to collect clinical and patient reported outcome data in an olaparib treated BRCAm+ PSR ovarian cancer population. Purpose: obtain prospectively real-world effectiveness, safety and treatment patterns data of patients with BRCAm+, PSR ovarian cancer in German hospitals and outpatient practices treated with Olaparib. Study Population 300 patients in 80 sites (approx. 40 hospitals and 40 outpatient practices) in Germany. Study Start Date: October 2015 Estimated Study Completion Date: June 2021 https://clinicaltrials.gov/ct2/show/NCT02503436?term=real+life+olaparib&rank=1

MATERIALS AND METHODS This is an observational, retrospective study, that will involve some Italian Hospitals from MITO group. Inclusion criteria histologically confirmed (high grade serous) non mucinous, non-borderline EOC; confirmed germline or somatic BRCA1 or BRCA2 deleterious mutations; age of > 18 years; platinum-relapsed EOC; two or more previous courses of platinum-based chemotherapy; objec­tive response (CR or PR) according to RECIST version 1.1 after last platinum-based therapy treatment with olaparib stan­dard dose from September 1st, 2015 to 31th January 2018. treatment with olaparib according to the conventional schedule of 400 mg (eight 50 mg capsules) twice daily, equivalent to a total daily dose of 800 mg continuously, or dose reductions as for clinician’s decision.

STATISTICAL ANALYSIS To describe: Descriptive statistics will be used to describe baseline char­acteristics, treatment patterns and adverse events. Endpoints: To describe: the efficacy of Olaparib monotherapy in terms of: percentage of patients that received olaparib for ≥6 months and ≥12 months from the beginning PFS; OS; ORR; TTF the safety of Olaparib monotherapy the incidence and management of main adverse events the use of dose reductions related to adverse events further treatments after progression and its efficacy MITO28/MANGO OV4 è uno studio multicentrico di fase II, non randomizzato atto a valutare sicurezza ed efficacia di Pembro nel trattamento chemioterapico di I linea in associazione a Carboplatino /Paclitaxel ed a mantenimento in monoterapia in donne affette da carcinoma ovarico, primitivo peritoneale o delle tube di Falloppio in stadio avanzato (FIGO III B-C-IV), o in recidiva chemio naive non candidate a ricevere Bevacizumab (per controindicazioni, rifiuto del paziente o scelta del clinico). Le pazienti riceveranno Pembrolizumab alla dose di 200mg d1q21, in associazione a Carboplatino /Paclitaxel d1q21 per 6 cicli ed a mantenimento come monoterapia fino ad un massimo di 22 cicli, PD o tossicità inaccattabile

COLLECTING DATA Data will be collected with Microsoft excel program database. For eligible patients all the informations of clinical interest will be collected (FIGO stage, age at diagnosis, type of primary debulking surgery, type of BRCA mutation, etc.) Privacy Policy Each center will assign and maintain the code and patient list to ensure privacy The full names of patients will be combined with a progressive registration number code assigned by every single center which will be shown in the header of all data collection forms and which will be used for all communications concerning the single patient

UPDATE CENTERS N° CASES 1 INT Milano 23 2 Ospedale Fazzi di Lecce 21 3 INT PASCALE Napoli 22 4 INT «Giovanni Paolo II» Bari 14 5 Università degli Studi di Bari 12 6 Università la Sapienza Roma TOTAL 104 MITO28/MANGO OV4 è uno studio multicentrico di fase II, non randomizzato atto a valutare sicurezza ed efficacia di Pembro nel trattamento chemioterapico di I linea in associazione a Carboplatino /Paclitaxel ed a mantenimento in monoterapia in donne affette da carcinoma ovarico, primitivo peritoneale o delle tube di Falloppio in stadio avanzato (FIGO III B-C-IV), o in recidiva chemio naive non candidate a ricevere Bevacizumab (per controindicazioni, rifiuto del paziente o scelta del clinico). Le pazienti riceveranno Pembrolizumab alla dose di 200mg d1q21, in associazione a Carboplatino /Paclitaxel d1q21 per 6 cicli ed a mantenimento come monoterapia fino ad un massimo di 22 cicli, PD o tossicità inaccattabile

TIMELINES OF THE STUDY Ongoing: approval ethics committee February 2018: study protocol submission to the MITO’s new protocols commission. February 2018 - April 2018: data collection MITO28/MANGO OV4 è uno studio multicentrico di fase II, non randomizzato atto a valutare sicurezza ed efficacia di Pembro nel trattamento chemioterapico di I linea in associazione a Carboplatino /Paclitaxel ed a mantenimento in monoterapia in donne affette da carcinoma ovarico, primitivo peritoneale o delle tube di Falloppio in stadio avanzato (FIGO III B-C-IV), o in recidiva chemio naive non candidate a ricevere Bevacizumab (per controindicazioni, rifiuto del paziente o scelta del clinico). Le pazienti riceveranno Pembrolizumab alla dose di 200mg d1q21, in associazione a Carboplatino /Paclitaxel d1q21 per 6 cicli ed a mantenimento come monoterapia fino ad un massimo di 22 cicli, PD o tossicità inaccattabile

CONTACTS Coordinator Center: Istituto Nazionale per la cura dei tumori IRCCS Fondazione “G. Pascale” Napoli Tel: 081 5903637 Fax: 081 5903861 Email: s.cecere@istitutotumori.na.it